Confab Reveals Prevention Gains

Antiretroviral treatment as prevention, long-acting HIV drugs, HIV cure research, and new treatments for hepatitis C were among the highlights discussed last week in Boston at the 21st Conference on Retroviruses and Opportunistic Infections, the largest annual HIV/AIDS medical meeting in the U.S.

Prevention Highlights

On the HIV prevention front, researchers reported that no one in a large study of same-sex and heterosexual couples was infected by a partner who was on effective antiretroviral treatment.

An analysis from the multinational PARTNER study included 767 serodiscordant or mixed-status couples -- about 60 percent heterosexual and 40 percent gay men -- in which the HIV-positive partner was on antiretroviral therapy with very low viral load (under 200 copies). Collectively, they reported more than 44,000 acts of vaginal or anal sex without condoms.

Over two years of follow-up, there were no cases of linked transmission in which the negative partner became infected with the same genetic strain of HIV as their primary partner. Without treatment, 50 to 100 new infections would have been expected. However, there were some new infections with different HIV strains, indicating that transmission happened outside the main relationship from sex partners who may not have been on treatment.

While these findings show that HIV treatment-as-prevention is highly effective, lead researcher Jens Lundgren from the University of Copenhagen emphasized that they do not mean transmission from a treated partner cannot occur. Statistical models suggest the odds of transmission may be as high as one in 10 for anal sex or one in 25 for vaginal sex over a 10-year period.

Whether this level of risk is acceptable "is not for us to say, but for people to decide," Lundgren said. But he stressed that there is "no reasonable legal action you can take against people for not using condoms" if they are on effective HIV treatment.

New HIV Drugs

Development of new HIV drugs has taken a back seat to biomedical prevention and hepatitis C treatment in recent years.

"At this stage of the epidemic, we’re focused on getting treatment to people who need it," Judith Currier from UCLA said at an opening press conference March 3.

But some researchers did present some promising new HIV treatment data.

Jay Lalezari from Quest Clinical Research in San Francisco reported on a novel HIV attachment inhibitor, Bristol-Myers Squibb’s BMS-663068, which blocks the first step of viral entry into cells. This multinational study included 253 treatment-experienced people with HIV, many of whom had drug-resistant virus.

After 24 weeks of treatment with BMS-663068 plus raltegravir (Isentress) and tenofovir (Viread), up to 80 percent had undetectable viral load, compared with 75 percent of people who took a triple regimen containing boosted atazanavir (Reyataz). BMS-663068 was well tolerated and there were no signs of safety problems.

"Speaking as an activist, I want to thank the company for bringing forth a new drug with a new mechanism of action," Lalezari said, adding that the drug could be especially beneficial for people with long-term HIV infection who need more treatment options.

Another study looked at a next-generation non-nucleoside reverse transcriptase inhibitor named doravirine (formerly MK-1439). After 24 weeks on treatment, 76 percent of people taking doravirine plus tenofovir/emtricitabine (the drugs in Truvada) had undetectable HIV, compared with 64 percent of those taking efavirenz (Sustiva) triple therapy. Doravirine had better tolerability overall, with fewer people reporting the kinds of central nervous system side effects often seen with efavirenz.

Finally, David Margolis from GlaxoSmithKline reported good safety and effectiveness in the LATTE study, which tested a two-drug regimen containing the new integrase inhibitor GSK744 plus rilpivirine (Edurant) used as maintenance therapy after people achieve full viral suppression using a standard three-drug regimen.

While this study tested daily pills, it sets the stage for future trials of long-acting formulations of both drugs that could potentially be administered once-monthly or even quarterly.

The long-acting injectable formulation of GSK744 may also be a future option for pre-exposure prophylaxis, or PrEP, as monthly injections may be more convenient and encourage better adherence than daily tenofovir pills.

Chasity Andrews and Gerardo Garcia-Lerma reported that the long-lasting shot protected monkeys from vaginal or rectal exposure to an HIV-like virus. A human trial of GSK744 injections for PrEP (HPTN 077) is now under way and will include a study site in San Francisco.

Search for a Cure

Cure-related research at CROI garnered some of the biggest headlines, but the new findings offer incremental clues about how HIV persists in the body rather than breakthroughs.

At last year’s CROI, Deborah Persaud from Johns Hopkins University reported on an infant in Mississippi born to an HIV-positive mother who did not take antiretrovirals to prevent mother-to-child transmission. Given the high-risk situation, the baby was started on combination antiretroviral therapy within 30 hours after birth. After 18 months the girl’s guardians removed her from care and she stopped treatment. But when she returned to care several months later, she still had undetectable viral load despite still being off antiretrovirals.

This year Persaud provided an update on the Mississippi case. The girl - now 3 years old and off treatment for two years - still has undetectable blood viral load and extensive testing has not found HIV in her peripheral blood cells or other reservoirs.

"We can conclude that this child remains in remission," Persaud said, suggesting that very early treatment for infants may restrict the establishment and spread of HIV in the body.

Persaud also described a second baby in Los Angeles County who also started treatment very early and appears not to have detectable HIV using the most sensitive tests. This child, however, has not been taken off antiretroviral treatment and does not yet represent another possible cure.

Also on the cure front, Timothy Henrich from Brigham and Women’s Hospital reported that detectable HIV has returned in two Boston bone marrow transplant recipients who for a time appeared to be controlling the virus without antiretroviral therapy.

The men received donated bone marrow, which contains stem cells that give rise to all blood cells, as treatment for lymphoma. The Boston patients received normal stem cells. That differs from the case of Timothy Brown, also known as the Berlin patient, who apparently remains HIV-free seven years after stem cell transplants from a donor with a double mutation (CCR5-delta-32) that makes cells resistant to viral entry.

In the Boston cases, after HIV could not be detected for 2.6 and 4.3 years, researchers agreed to try an experimental treatment interruption to see if the virus would return. As Henrich first reported last December, this did occur, after 12 weeks and eight months off treatment.

These cases suggest that curing HIV will be difficult if even a tiny amount of residual virus remains in the body.

"We believe [viral] rebound from only one or a few cells is enough to cause detectable virus," Henrich said, suggesting that a functional cure will likely require a combination of approaches.

Hep C Revolution

Hepatitis C treatment is now a major theme of CROI, at a time when next-generation direct-acting antivirals are entering clinical use and interferon-free treatment is becoming a reality, curing more people in a shorter time without the difficult side effects of interferon.

The first of these drugs - Gilead Sciences’ sofosbuvir (Sovaldi) and Janssen’s simeprevir (Olysio) - were approved late last year. Douglas Dieterich from Mt. Sinai said that sofosbuvir has been "flying off the shelves" at a rate of about 2,000 prescriptions per week.

Researchers presented data from several studies showing high rates of sustained virological response - considered a cure - for both people with hepatitis C alone and those with HIV and hepatitis C virus (HCV) coinfection.

For example, a 12-week combination of three direct-acting antivirals being developed by AbbVie (formerly Abbott) cured 99 percent of previously untreated people with HCV genotype 1b. This regimen could be approved by the end of the year. Another 12-week, three-drug oral regimen containing Bristol-Myers Squibb’s daclatasvir cured 92 percent of treatment-naive patients, most of whom had harder-to-treat HCV genotype 1a.

Results from the National Institutes of Health’s SYNERGY study showed that treatment might be shortened even further - to just six weeks - for some patients.

This study enrolled mostly low-income African American patients in Washington, D.C., many of whom had HCV genotype 1a and advanced liver fibrosis or cirrhosis.

"We believe this population is really reflective of the hepatitis C population in the U.S., which historically has been a difficult-to-treat population," said lead researcher Anita Kohli.

Participants were treated with a coformulation of sofosbuvir and ledipasvir for 12 weeks, or with triple combinations adding another experimental Gilead drug (GS-9669 or GS-9451) for six weeks. Cure rates were 95 to 100 percent and treatment was well tolerated.

"This short duration simple therapy for HCV may prove relevant for the global elimination of hepatitis C, where uncomplicated, well-tolerated therapy is required to ensure adherence and minimize health care expenditures," the researchers concluded.

Several other studies showed that cure rates and side effects were the same in HIV/HCV coinfected patients as in people with hepatitis C alone - good news because HIV-positive people with hepatitis C typically have more rapid liver disease progression and do not respond as well to interferon.

While these results are impressive, there are still barriers to successful hepatitis C treatment in the real world, including inadequate HCV screening, a shortage of knowledgeable providers, and the high cost of new drugs.

Hepatitis C treatment is currently a "dribble" rather than a cascade, said Tracy Swan of the Treatment Action Group at an annual treatment activism lecture named after Project Inform founder Martin Delaney.

While hepatitis C has the benefit of a cure, it is lacking the political will, global collaborations, government-funded research networks, funding for care and treatment, and community identity that have turned around the HIV epidemic. "One thing HIV has taught us," Swan emphasized, "is that the community response is absolutely essential to transforming an epidemic."

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